Modafinil, C15H15NO2S, also known as 2-(benzhydrylsulfinyl) acetamide, or 2-[(diphenylmethyl) sulfinyl] acetamide, is a synthetic acetamide derivative with wake-promoting activity, the structure and synthesis of which has been described in French Patent No. 78 05 510 and in U.S. Pat. No. 4,177,290. Modafinil has been approved by the United States Food and Drug Administration for use in the treatment of excessive daytime sleepiness associated with narcolepsy, and is marketed under the name Provigil®. Provigil® is a pharmaceutical product comprising tablets containing 100 mg or 200 mg of modafinil.
The current invention provides an efficient process that allows for commercial manufacture of modafinil. The present invention discloses a process in which benzhydrylthiol is reacted with chloroacetamide to obtain the corresponding benzhydrylthioacetamide.
A synthesis of modafinil has been described in U.S. Pat. No. 4,177,290, where benzhydrol was reacted with chloroacetic acid.
A related process for synthesizing the levorotatory isomer of modafinil is disclosed in U.S. Pat. No. 4,927,855, issued May 22, 1990.
Processes for synthesizing modafinil derivatives are disclosed in U.S. Pat. No. 4,066,686, issued Jan. 3, 1978; U.S. Pat. No. 4,489,095, issued Dec. 18, 1984; U.S. Pat. No. 5,719,168, issued Feb. 17, 1998; PCT Publication No. 01/15752; and U.S. patent application Ser. No. 10/014,645.
Processes describing reaction of benzhydryl halides with 2-mercaptoacetates were described in U.S. Pat. No. 5,571,825; 4,964,893; EP Pat. No. 0,528 172; and Chinese Journal of Medicinal Chemistry,1999, 9, 132 .
Processes for preparing modafinil have been described in PCT Publication No. 02/10125.
The present invention provides an efficient process for the preparation of modafinil, which offers significant commercial advantages when preparing modafinil on an industrial scale. The current invention produces modafinil with fewer steps and at enhanced yields. Use of the chloroacetamide in the second step of the instant invention directly adds the desired amide group to the final product in one step. A further advantage of the instant processes is that the four reaction steps can be conducted in one reaction vessel, without isolation of the intermediates. This reduction in steps and the efficiency of the reaction steps also result in enhanced yields. An additional benefit of the present processes is a reduction in the undesirable waste products.
The current processes further provide for significant efficiencies in the commercial manufacture of modafinil. The overall costs and hazards of the manufacturing process are reduced, as simpler machinery can be used, less labor is involved and fewer undesirable waste products are generated, all of which provides distinct commercial advantages for the preparation of modafinil on a commercial scale.